Optogenetic hub cell control for no seizures, no side-effects in temporal lobe ep

描述(申请人提供)：颞叶癫痫是成人中最常见的癫痫形式。目前已有的抗癫痫药物往往具有显著的、使人衰弱的副作用，而颞叶癫痫往往对药物治疗产生抗药性，这是一个巨大的社会和医学问题。这项拟议研究背后的中心思想是，有可能通过仅在关键时刻暂时抑制少量独特神经元的活动来实现癫痫控制，这些神经元可能主要负责触发边缘系统的癫痫发作。我们最近的大规模计算机模拟研究表明，罕见的、异常的、超连接的、中枢样神经元可能在癫痫发作的启动中发挥关键作用。随后，这种中枢细胞在健康发育的海马体中被证明，而且已经表明，在切片中调制单个中枢细胞可以阻止整个网络的自发爆发活动。在这里，我们建议使用新的光遗传学方法在体内选择性地抑制癫痫成年小鼠齿状回和内嗅觉皮质中异常的中枢样细胞，以防止内嗅脑-海马网内的连合-联合和临时-氨化通路的过度激活，特别是在自发性反复发作开始时。由于操作只会以时间选择性的方式影响整个边缘系统中的少数细胞，因此可以在对电路的正常信息处理影响最小的情况下实现有效的癫痫控制。如果成功，这项拟议的研究将展示一种全新的方法，以实现癫痫治疗“没有癫痫发作，没有副作用”的目标。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is the most common form of epilepsy in adults. Currently available anti-epileptic drugs often have significant and debilitating side-effects, and temporal lobe epilepsy frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. The central idea behind the proposed research is that it may be possible to achieve seizure control by transiently inhibiting, only at critical moments, the activity of a low number of unique neurons that may be primarily responsible to triggering seizures in the limbic system. Our recent large-scale computational modeling studies have shown that rare, abnormal, super- connected, hub-like neurons may play a key role in seizure initiation. Subsequently, such hub cells have been demonstrated in the healthy developing hippocampus, and it has been shown that modulation of single hub cells in slices can block the spontaneous bursting activity of the entire network. Here we propose to use novel optogenetic approaches to selectively inhibit abnormal hub-like cells in the dentate gyrus and entorhinal cortex of epileptic adult mice in vivo in order to prevent the hyper-activation of the commissural-associational and temporo-ammonic pathways within the entorhino-hippocampal network specifically at the onset of spontaneous recurrent seizures. Because the manipulation will affect only a few cells in the entire limbic system in a temporally selective manner, effective seizure control may be achieved with minimal effects on the normal information processing of the circuit. If successful, the proposed research will demonstrate a fundamentally novel approach to achieving the goal of "no seizures, no side-effects" for the treatment of epilepsy.